DDNews caught up recently with Dr. Daniel Cohen, CEO and co-founder of Paris-based Pharnext, a clinical biopharmaceutical company working on drugs for a range of neurodegenerative diseases both common and rare—including Parkinson’s disease and Charcot Marie Tooth disease (CMT1A). Pharnext takes a proprietary approach to drug development, known as Pleotherapy.

Pharnext’s PXT3003 is in late-stage Phase 3 trials with the U.S. Food and Drug Administration for CMT1A, a debilitating rare disease for which there is no satisfactory treatment yet available. Pharnext has also developed a drug addressing diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, PXT 864, which is in Phase 2 trials and has achieved encouraging results so far.

Cohen is an internationally recognized scientist who has been at the forefront of genetic research for more than 30 years. In the mid-1990s he led the team that created the first physical map of the human genome at the Fondation Jean Dausset. Later, he and several colleagues were instrumental in creating the genome-wide association study (GWAS) process—large-scale genome wide genetic analysis.

DDNews: How did your leadership in the creation of the human genome map influence your thinking about developing treatments for rare diseases?

Daniel Cohen: As a pioneer in human genome mapping, I knew that genomics would bring new inspiration to new drugs. Now we need to add to the monotargeted approach and combine drugs for multifactorial tools. We can be repositioning or repurposing drugs, because we know that any molecule can have a different function.

Pharnext uses human genetics data for its platform. By obtaining information on patients and existing drugs, we come up with synergistic combinations. Because there is no need to design new drugs, we shorten the development process by many years.

DDNews: How did Pharnext evolve?

Cohen: Pharnext is 11 years old. Our vision has been to focus on combinatorial medicine, rather than a monotargeted approach. We came up with a platform to develop all of our products. We develop drugs synergistically, using lower doses with repurposed and combined drugs.

DDNews: How did the concept of Pleotherapy evolve?

Cohen: Pleotherapy assumes that any molecule can be used for different functions. The Pleotherapy approach combines low doses of existing drugs to develop treatments for new indications using big data analysis of genomics and pharma, to match the properties of drug combinations with specific diseases. Pharnext’s use of drugs that have been approved by the FDA, combined with its proprietary data analysis, allows the company to shave as much as seven years off the typical 15- to 20-year drug approval process.

DDNews: What are the benefits of Pleodrugs?

Cohen: These novel therapeutics called pleodrugs are developed at new optimal lower doses and under new formulations. They offer several key advantages: efficacy, safety and intellectual property including several composition-of-matter patents already granted.

DDNews: How did the concept of network pharmacology evolve?

Cohen: We realize that the body is a network of molecules that are interconnected, physically and functionally. It is a complex network with fragilized zones in certain diseases in certain patients. Alzheimer’s and diabetes share some fragilized zones, as do Alzheimer’s and ALS. We have to figure out which fragilized zones are targets of known drugs. Artificial intelligence (AI) can be used to mine big data. Then within the fragilized zones we use drugs experimentally and combine them and test them in humans.

DDNews: How can biopharmaceutical companies do a better job of finding cures for orphan diseases?

Cohen: AI makes it easier to find potential drugs for experiments. There is an overflow of data from sequencing and literature. Diagnosis is easier, because you know what you can do, but there is a lot of missing data. We have to educate the computer with data, infer output, train the computer to look for new targets and then repurpose the drugs for broad use.

DDNews: How does PXT3003 work, in general terms?

Cohen: Charcot-Marie-Tooth (CMT) disease is the degeneration of the muscle of the peripheral nerves, rendering people unable to walk or write. It is caused by the overexpression of protein that affects myelin surrounding the nerves. We build a molecular network and use the drugs together in the nerve, muscle and inflammatory cell to lower toxic protein. The drug has a broad mechanism of action to stop the decline and improve what the patient can do.

In preclinical studies in two different rodent models, PXT3003 inhibited the overexpression of the PMP22 gene, improved myelination of peripheral nerves and clinical/sensory impairments. In a Phase 2 clinical trial in 80 adult patients with CMT1A, PXT3003, beyond stabilization, improved multiple efficacy endpoints, particularly the ONLS score (Overall Neuropathy Limitation Scale) which measures patient disability. The U.S. FDA suggested the use of ONLS as a primary efficacy endpoint in clinical trials in CMT. In addition, PXT3003 was safe and well tolerated.

DDNews: What is the timeline for PXT3003?

Cohen: Phase 2 has looked good. Phase 3 studies are now enrolling in Europe and the United States in 30 centers. Phase 3 top-line results expected in the second half of 2018 for CMT1a in adults. A Phase 3 launch is expected for CMT1a in pediatrics.

DDNews: How does PXT864 work?

Cohen: This is another combination of two drugs with a new mechanism of action. PXT864 is a synergistic combination of baclofen and acamprosate given as a pill twice a day. PXT864’s main mechanism of action is the restoration of balance between excitatory (glutamate activity) and inhibitory (glycine and GABA activity) pathways, disrupted by toxic factors such as Aβ oligomeric peptides in Alzheimer’s disease. PXT864 showed positive safety and tolerability results in a Phase 1 clinical trial that enrolled 24 healthy volunteers.

Cohen: Further Phase 2 studies are planned for Alzheimer's disease, Parkinson’s disease and amyotrophic lateral sclerosis. We hope to partner with a big pharma company.

DDNews: What kinds of partnerships is Pharnext developing?

Cohen: Pharnext has two pipelines. We are working with two partners to combine drugs, find new compounds and find new targets based on the platforms we are building.

DDNews: What is the commercial potential of the drugs in the Pharnext pipeline?

Cohen: Alzheimer’s disease affects around 44 million people worldwide. Its potential is in the multibillions. CMT is a rare disease, but there are 100,000 patients in the United States and Europe. It could be a billion dollar drug but still affordable to those who need it.